PubMed is a database of original journal articles in basic biological sciences and medicine maintained by the National Institutes of Health (NIH). I am, by virtue of my education as well as my temperament, a PubMed addict. That is to say, in researching my medical care, I like to go straight to the horse's mouth. So today, in the spirit of sharing what I learn in my digging and in hopes of said digging benefiting others, I am inaugurating a new periodic series at Glow in the Woods-- PubMed Says. For the first installment of the series, I am discussing an issue of interest in managing a subsequent pregnancy-- intrauterine infections with group B streptococcus (GBS).

Our immune systems are really a wonder of efficiency and adaptability. In fact, they are essentially mini-evolution machines, running in real time. You see, with the number of pathogens we have the potential to encounter in our environment, encoding even a single fighter molecule for each of these would require more genes than we have in our entire genomes. Not to mention that pathogens evolve just like everything else (think new strains of flu every year), and so having static defenses is only marginally better than having no defenses at all. Ok, let me qualify that-- we have static immune systems too (skin being the biggest organ and biggest participant in that system), and we would not be able to hold off the assault of all the pathogens we encounter in our daily lives without that innate immune system. But neither could we do without the adaptive one-- the one we hear the most about, the one that has those famed antibodies as major players.

Antibodies are molecules made by the cells of our adaptive immune system that can recognize specific portions of specific pathogens. They are generated randomly, but according to rules-- one component of each specified type is picked randomly, and components are assembled in specified order. Sometimes the joining of the components is a bit off, which provides for even more variability.

Everything in biology happens via interaction of surfaces, tiny, microscopic shape fitting. Molecules are themselves signals, and their interaction is the passing of that signal. That, combined with the vast number of antibodies we generate, means two important things: 1) we can (and do) generate antibodies to pathogens we have never encountered before, to pathogens no-one has encountered before; and 2) we can and do generate antibodies that recognize our own molecules, molecules that are working hard to keep us chugging along. That last possibility is a problem, and the basis of autoimmune disorders.

So the reason autoimmune disorders are actually rare is that we also have a great way of "teaching" our immune system about self vs. non-self. We need it to know not to generate antibodies to self, only to the things that we would encounter from the outside, the non-self, the potential pathogens.

And this is finally where this little discussion becomes relevant to pregnancy-- the self vs. non-self education thing? It happens perinatally. Very loosely speaking, while the baby is cooking, the immune system is set to assume that everything it encounters is self, and so it kills off all the cells that would produce antibodies that can interact with these self molecules. At birth, the switch gets flipped, and the system gets reset to assume that everything new it encounters from then on is non-self, pathogen, signal for search and destroy. Pretty cool, right?

Well, there is one teensy-weensy problem. The problem, of course, is that baby in utero effectively has no functioning immune system. Ooops. But the good news is, the baby is in the sac that is in the uterus, and no pathogens are supposed to be able to get into the intact sac. And for most women, that is exactly how it goes. The bad news is that for some women some infections can get in, with fatal consequences.

This question is of special interest to me because my son A was infected with one of these infections, Group B Strep (GBS), and the pathologist ruled that to be a contributing factor in his death. Beyond the "what happened?" question, history of infections in the intact sac also have serious implications for any subsequent pregnancy, and that is why I chose this topic today.

The case described in the paper is sad and tragic, and all too familiar to many of us here-- normal pregnancy with some minor causes for concern throughout, resulting in fetal death and stillbirth in the 40th week of gestation. Although the text uses medical jargon, the upshot is that upon delivery the baby looked fine, with only the skin changes as a sign of having been dead for about a day being notable. In other words, without an autopsy there would have been no explanation for this tragedy, and no information to guide the family in making decisions about a subsequent pregnancy.

Multiple causes of stillbirth were considered, including fetal anomalies (ruled out by autopsy), maternal disease (discussed and found unlikely due to medical history), unexplained (always popular, no?), and fetal infection. According to the literature, infections account for approximately 10-25% of stillbirths, with significantly higher rates in economically depressed areas and in developing countries.

In light of what I said above, it should be pretty clear that any infection that can breach the sac is likely to lead to unfortunate consequences. Infections can be caused by bacteria, viruses, fungus, or protozoa. In addition to direct fetal infection, infections may also cause stillbirth via placental damage or severe maternal illness. There are very few pharmaceutical agents available to treat viral infections even in adults, and as far as I know there is not much that can be done for a fetus infected with a virus. Yeast (a fungus) and various protozoa have been reported as causes of stillbirth, but extremely rare causes. What I want to do here is focus on bacterial infections, and GBS infections in particular, and then discuss management of a subsequent pregnancy if a diagnosis of infection as a primary or secondary cause of stillbirth was made or suspected.

GBS is known to be common in genital tract, and a large percentage of healthy adult women are colonized, i.e. have GBS in their vagina or lower intestine (This meta-study from Europe shows rates of colonization of 6.5-36% with great geographic variability) . Recognition of GBS as a human pathogen did not occur until 1960s. In the 1970 it was recognized as a leading cause of neonatal infection and an important cause of maternal uterine infection. Since then, screening protocols have been put in place to identify women colonized with GBS, and antibiotic treatment during labor is recommended for women found to be colonized. These treatments are aimed at reducing the rate of neonatal infection, and establishing these guidelines has led to a marked decrease in early neonatal GBS infections.

In addition, and more relevant to our discussion here, 4-10% of stillbirths in United States and Europe are thought to be caused by GBS infections. Thus it is known that GBS can cross intact membranes and cause infection of amniotic fluid and/or fetus. In addition, GBS is associated with some cases of PPROM, and in at least one study, for at least one population, has been shown to be the leading cause of PPROM.

GBS, like other bacterial infections known to cross the intact membranes and cause stillbirth and other adverse perinatal outcomes, is an ascending infection, meaning that it rises up from mother's vagina, anus, or rectum, to the uterus. In most cases, infection occurs after the rupture of membranes, and that is why the guidelines for treatment of colonized mothers call for treatment with antibiotics while in labor.

As I mentioned above, this is an adequate protocol for most mothers. However, for those of us who have had infection, particularly bacterial infection, ruled to be a cause of stillbirth or PPROM, it is wise to consider additional measures in a subsequent pregnancy. I would, in abundance of caution, also suggest that families where the cause of stillbirth was unexplained, particularly those who did not have an autopsy performed, or whose autopsy did not include a report on possible infections, consider these additions to their subsequent pregnancy care protocol.

The NEJM paper, after providing fairly conclusive evidence for GBS being the cause of the stillbirth in the particular patient, includes the following possible interventions (beyond the general guidelines referenced above) aimed at attempting to prevent a recurrence of stillbirth caused by GBS:

Screen for GBS rectovaginally early in pregnancy and suppress or eradicate detected colonization with antibiotics. (It is worth noting that colonization with GBS can be intermittent, that treatment is not always successful at completely eradicating colonization, and that re-colonization occurs in up to 40% of subjects within 4 weeks.)

Screen for GBS in patient's sexual partners and suppress or eradicate detected colonization with antibiotics. (Same caveats as above.)

Advise abstinence or condom use. (Evidence that GBS is sexually transmitted is weak. In the words of the article authors, "Both interventions are relatively harmless, but compliance may be poor.")

Vaccinate the mother. (No vaccine is currently available. If it does become available in the future, it will not protect fetuses before 32 weeks of gestation because IgG antibodies that would be the actual mechanism of the protection are transferred across the placenta only poorly before that gestational age.)

My own protocol for my ongoing pregnancy includes early and frequent urine screenings for GBS and other bacteria. If and when any are found, I am treated with antibiotics in hopes of preventing an intrauterine infection. This intervention was proposed by my OB, with the caveat that there have not yet been studies to show the effectiveness of this prevention method. I was more than happy to agree to this protocol, as this is pretty much the only thing we can actually do to try to prevent a recurrence.

Obviously this protocol is most useful for tracking GBS and other bacterial pathogens. I have not done enough research to comment on what measures might be able to prevent a recurrence of other types of infection. However, in the abundance of caution category, I would suggest that it might be wise to treat the ability of any type of previous ascending infection to cross the membranes as a red flag for the possibility of other ascending infections being able to do the same in subsequent pregnancies, i.e. that it might be useful to apply the protocol for attempted prevention of bacterial infection in cases where other infections were implicated in a previous pregnancy. This is a conjecture on my part. I do not know of any studies that quantify risks of different infections following a previous case of any given infection. However, each one of us, in each of our subsequent pregnancies, is concerned with the sample size of exactly one, and therefore, we, in consultation with our health care providers, can and should decide which protocols would give us peace of mind in addition to which are incontrovertibly scientifically justified.

I hope you found this useful, or, at least, interesting. If you have ideas for future installments of this series, please let me know.

*I can not place a pdf of the paper in public domain here. But I do have it (as well as the pdfs of the other papers mentioned in this entry) , and if you are interested, please email me through our contacts page, and I will be happy to send it to you.

glow in the woods

Bereaved parents of lost babies and potential of all kinds: come here to share the technicolour, the vividness, the despair, the heart-broken-open, the compassion, and the other side of getting through this mess called grief.

Parents of lost babies and potential of all kinds: come here to share the technicolour, the vividness, the despair, the heart-broken-open, the compassion we learn for others, having been through this mess — and see it reflected back at you, acknowledged and understood.